News & Research

Research Description

Obesity and more complex condition metabolic syndrome, which are currently epidemic in our country have been linked with the increase in consumption of sugars, especially added sugars containing fructose, such as sucrose and high fructose corn syrup (HFCS). These studies should help elucidate the novel mechanisms by which initial steps of the metabolism of consumed fructose mediate metabolic syndrome including activation of pathways of fat accumulation, inflammation and oxidative stress that drive both obesity and insulin resistance and lead in many cases to the development of type 2 diabetes. This will provide insights into mechanisms, which make fructose-containing sugars more dangerous for the development of the prodiabetic conditions. In addition, they will be useful for developing new therapeutic approaches for the prevention and treatment of obesity and metabolic syndrome.

Research Profile

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes?

Obesity and metabolic syndrome, which are currently epidemic in our country, have been linked with the increase in consumption of sugars, especially added sugars containing fructose, such as sucrose and high fructose corn syrup (HFCS). Fructose is distinct from other sugars in its initial metabolism, which starts with a biochemical reaction called fructose phosphorylation.  Ketohexokinase (KHK) is the enzyme responsible for this reaction, and it is different from the enzymes involved in the initial metabolism of glucose, another sugar commonly present in our diet.  Importantly, this enzyme is very active but poorly regulated in the cell. Feeding substantial amounts of fructose (consumed with soft drinks and foods sweetened with table sugar or HFCS) into cellular metabolism can cause rapid accumulation of excessive fat stored in the liver and in the visceral adipose tissue.

In contrast to glucose, these initial steps in the metabolism of fructose can deplete cellular ATP followed by increased intracellular production of uric acid, a waste product of metabolism of purines in the cell, which are a structural component and a final product of the degradation of DNA, RNA, and ATP. In its extreme, uric acid can form crystals and cause the debilitating disease gout; however, this is not directly related to fructose consumption. Our group has discovered that when we lower uric acid levels in blood, we can substantially improve insulin resistance in obese mice with the metabolic syndrome and reduce proinflammatory changes in the visceral fat, which is a common contributor to insulin resistance. 

In this project, we propose to characterize the molecular mechanisms by which purine degradation, induced by a high-fructose diet, can facilitate fat accumulation and cause a stress response in the cells via oxidative - and endoplasmic reticulum (ER) stress response. Our studies should help to elucidate the mechanisms by which the initial steps of the metabolism of consumed fructose can induce metabolic syndrome, including the activation of pathways of fat accumulation, inflammation, and oxidative stress that drive both obesity and insulin resistance and lead, in many cases, to the development of type 2 diabetes.  This will provide insights into the mechanisms, which make fructose-containing sugars dangerous for the development of prodiabetic conditions. In addition, our studies will be useful for developing new therapeutic approaches for the prevention and treatment of obesity and metabolic syndrome.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

We believe that our project will help you reverse your pre-diabetes or lessen the severity of your type 2 diabetes through further improvement of dietary recommendations. In fact, if you are obese and have insulin resistance or type 2 diabetes, even at this early stage of our research we would strongly encourage you, in addition to maintaining a diet with low glycemic index, to completely avoid food products and beverages sweetened with fructose-containing sugars (high fructose corn syrup and table sugar). There is a good chance that you will feel better quite soon without any side effects because you will be able to avoid all detrimental effects of fructose in addition to maintaining your normal glucose level. Fructose does not induce high blood glucose or insulin levels but it is still dangerous for you when consumed excessively. 

In addition, we believe that our project will provide a substantial background for the recommendation to use the already-available and inexpensive test of uric acid levels in patients with metabolic syndrome and type 2 diabetes and, if the uric acid levels are elevated, to consider the uric acid lowering therapy in addition to the other treatments patient is receiving in order to improve his or her condition. Finally, we believe that our project will likely elucidate a novel mechanism that might be important for development of the metabolic syndrome and its progressing to type 2 diabetes. This way our project will contribute to our scientific knowledge and understanding diabetes and underlying mechanisms.

 Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts?

I am a basic scientist with long-term interest in signal transduction and lipid and adipocyte biology. Therefore, literature on the mechanisms of obesity, metabolic syndrome, and type 2 diabetes is always on my reading list. The epidemic of diabetes and obesity is a terrifying problem which has been unfolding on my watch for more than two decades. My previous research project, funded by American Heart Association, was related to the role of hyperuricemia (high blood levels of uric acid) in cardiovascular risk. In particular, we discovered that uric acid has detrimental effects in adipocytes. We also showed that lowering uric acid in obese animals reduced production of proinflammatory factors in the adipose tissue and increased production of adiponectin, an adipocyte-specific factor with insulin-sensitizing activity. This treatment also improved blood pressure and insulin sensitivity in obese animals.  I knew that uric acid is a byproduct of the metabolism of fructose, which is abundant component of foods and drinks in the modern world, and I knew about the high quality clinical research of several scientists including Peter Havel and epidemiologist of metabolic diseases George Bray, who warned about the adverse effects of increasing consumption of fructose on human health and its potential role in the epidemics of obesity and diabetes. 

For these reasons, I felt that I could not stand aside, especially if I might be able to do something about it. Knowing that diabetes (and other diseases associated with obesity) cause a lot of human suffering and could eventually deplete health care budget of the country as powerful as United States, how anyone can stand aside? Not everyone believes that consumption of high fructose food and drinks can really play such a serious role in these epidemics. This is why my collaborators and I decided that we will do everything we can to find the truth, and if our hypotheses are confirmed, we will try to make it known to all people who may suffer from this as well as to those who is trained to help them. I am a member of American Diabetes Association, and I know that there is no better place than the American Diabetes Association to do this, and we are honored that we have a chance now to do this research with the support of this organization.

In what direction do you see the future of diabetes research going?

Research in the field of diabetes is becoming immensely complex. It encompasses studies from epidemiology and genome-wide associations to mechanisms of signal transduction from insulin receptor and all the increasingly complex signaling networks in the cell that potentially can affect insulin receptor signaling in a negative or positive way.

Researchers are also looking for some remedies in plants and exotic foods, among other things. In my opinion, this complexity will increase with the development of biology, including systems biology, bioinformatics, genomics, and cell biology. This is why it is very important to look also not only for new smart drugs affecting these complex pathways in the cell, but also for some relatively simple ways of prevention of this disease, especially in the case of metabolic syndrome, which is still can be reversed and prevent type 2 diabetes.

On the opposite side of the diabetes research, it is equally important to look for new and more efficient ways to better convince people to exercise and to maintain a healthy diet. Our developing knowledge should be spread to make everyone aware what the risks of this disease are in the modern world, especially for our children.